We note that endothelial activation occurs in HbSS by age 2 years, and that markers such as sVCAM-1 and sE-selectin correlate with LDH, a marker of intravascular hemolysis (r=0.6, p<0.000001, n=79) and not with F cell levels (r=o.18, p=0.1). Clinical evidence of microvessel disease and silent CNS infarction in the young child with HbSS also suggests that endothelial dysfunction begins early in life, making us acutely aware that modulating hemolysis and inflammation are at the forefront of sickle cell patient care. Besides the use of Hydroxyurea (HU), many other interventional therapies have not fulfilled early promise. The n-3 fatty acids, eicosapentaenoic (EPA;20:5) and docosahexaenoic (DMA;22:6) acids have pleiotropic effects protecting erythrocytes from hemolysis induced by oxidative stressors;modulating ischemia-reperfusion injury by the production of a novel series of potent metabolites, the Resolvins and Protectins which stop the clock on inflammation (Serhan, Ann Rev Immunol 2007;25:101-137);inhibiting the proinflammatory transcription factor NF-icB, and platelet and monocyte activation;and decreasing thrombin production. A report, in 2001, of 10 adults with various SCO syndromes treated with n-3 supplementation showed a 50% reduction in pain. The less than rigorous documentation of pain, emphasis on platelet inhibition, and inclusion of individuals with high baseline Hbs prevented the emergence of other non-hemostatic observations. A recent report demonstrates a deficiency in n-3 fatty acids in the membranes of the cellular elements of blood in HbSS, with a correlation between RBC membrane n-3 and Hb. This report, the short time it takes for n-3 supplements to replenish n-3 in cell membranes, the known pleiotropic effects of these relatively non-toxic physiologic fatty acids, and the transformation in vivo of EPA and DHA into potent anti-inflammatory metabolites, has led us to the rational decision that a clinical trial of n- 3 supplementation should be performed in HbSS. We will conduct (Aims I &II), a double-blind, placebo-controlled Phase II Trial to test whether oral daily supplementation with EPA (45mg/kgm) and DHA (37mg/kgm) for 6 months versus placebo will effect pain parameters (primary endpoint). We will, in addition (secondary endpoints) assess the effects of n-3 supplementation on various red cell parameters (hemolysis, response to oxidant stress, dense cell and PS+ cohorts, adhesion, NO bioavailability and flow-mediated vasodilation);white cell parameters (inflammatory and antiinflammatory products of AA, DHA and EPA, including LKTs, and novel Resolvins and Protectins in collaboration with Dr. Serhan);various endothelial and platelet activation markers, and thrombin generation. We hypothesize that n-3 PUFAs will decrease vasocclusion-induced pain, dependent on a combination of effects on hemolysis, adhesion, inhibition of cell activation and production of anti-inflammatory modulators. In Aim III, we will evaluate RBC membrane fatty acid profiles in HbSS disease (ages 6 months to 12 years) to pinpoint the temporal sequence at which this n-3 deficiency occurs such that a follow-up EPA/DHA supplementation study in this vulnerable childhood population can be conducted at a later date. The study is thus translational in its true sense, including a direct intervention with potential to modify clinical care, while simultaneously providing a mechanistic evaluation of the effects of n-3 in HbSS using state-ofthe- art methodologies, and a team whose skills have been honed by previous CSCC Clinical Trial experience.